Abstract
Separation of micro- and nano-sized biological particles, such as cells, proteins, and nucleotides, is at the heart of most biochemical sensing/analysis, including in vitro biosensing, diagnostics, drug development, proteomics, and genomics. However, most of the conventional particle separation techniques are based on membrane filtration techniques, whose efficiency is limited by membrane characteristics, such as pore size, porosity, surface charge density, or biocompatibility, which results in a reduction in the separation efficiency of bioparticles of various sizes and types. In addition, since other conventional separation methods, such as centrifugation, chromatography, and precipitation, are difficult to perform in a continuous manner, requiring multiple preparation steps with a relatively large minimum sample volume is necessary for stable bioprocessing. Recently, microfluidic engineering enables more efficient separation in a continuous flow with rapid processing of small volumes of rare biological samples, such as DNA, proteins, viruses, exosomes, and even cells. In this paper, we present a comprehensive review of the recent advances in microfluidic separation of micro-/nano-sized bioparticles by summarizing the physical principles behind the separation system and practical examples of biomedical applications.
Highlights
The development of efficient and effective techniques for bioparticle separation leads to the development of innovative technologies and tools for biological sensing/diagnostics, as well as other biochemical processes in pharmaceutical, life sciences, and clinical analysis [20,21,22,23,24]
In terms of sample preprocessing for biosensing, a small sample volume may not be a big issue, but in terms of an actuator that needs to continuously separate samples, there is still a somewhat large gap between the capacity processed in microchannels (~few μL/min) and the throughput required by the industry (>few L/min)
A separation technique based on fast hydrodynamics, such as inertial microfluidics, seems to be the most suitable, and multilayered, massively parallelized microfluidic separation devices can be a solution [40,179,180]
Summary
Various microfluidic techniques have been developed to accurately control micro-/nanoscale bioparticles, such as trapping [1,2,3], focusing [4,5,6], compartmentalization [7,8,9,10], preconcentration [11,12,13], and separation [14,15,16] using mechanical, optical, magnetic, electrical, or chemical forces, resulting in improving the performance of biosensors [17,18,19]. Among the various particle manipulation techniques, separation of micro-/nanoscale bioparticles seems to be one of most essential processes for highly sensitive and selective biosensing and biochemical analysis of complex bio-samples, such as blood, which contains cells, bacteria, viruses, proteins, DNA molecules, and other biological ingredients. The conventional method has an inevitable limitation in that it is difficult to separate particles in a continuous and autonomous manner as a batch process that operates periodically. It seems to be unsuitable for separating bioparticles contained in a small amount of difficult-to-obtain biofluids or expensive/rare samples. It is much easier to be developed as an all-in-one device that simultaneously performs sample preparation, including separation, preconcentration, and biosensing/bioanalysis, directly connecting the pretreated sample to downstream biosensors without additional processing [18,21,22,31,32,33]
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